Dendritic cells (DC) are specialized antigen presenting cells (APC) that are critical for initiating and regulating adaptive immune responses. Although distinct DC subsets are present throughout peripheral tissues, their functional roles remain poorly understood. In the intestine there are two major APC populations that can be defined by the surface expression of CX3CR1 and CD103. CX3CR1 are thought to be a non-migratory macrophage-like population. In contrast, CD103+ DC migrate to mesenteric lymph nodes, where they carry out classical DC functions. In vitro, migrated CD103+ DC can induce regulatory T cells, suggesting a mechanism whereby the immune system can become tolerant to normal intestinal contents. It has recently been appreciated that the CD103+ DC population actually contains two distinct subsets distinguished by CD11b expression. We have generated mice with a selective ablation of the CD103+CD11b+ subset and have bred them with previously described mice that lack CD103+CD11b- DC. By comparing mice lacking one or both DC, this proposal seeks to determine the precise functional role of each subset in vivo. Our central hypothesis is that these two CD103+ populations are mutually redundant for the development of tolerance. However, in the setting of infection, we hypothesize that CD11b+ DC are required for innate mucosal defense and the development of Th17 responses, while CD11b- DC mediate Th1 immunity. This study thus has important implications for our understanding of intestinal immune homeostasis and immune responses to gut pathogens. PUBLIC HEALTH RELEVANCE: Project Narrative Tissue resident dendritic cells control the balance of immune tolerance versus inflammation. This study will uncover the ability of unique intestinal dendritic cell populations to generate appropriate immune responses in both the steady state and disease.